1. Field of the Invention
The field of the invention relates to cancer biology. The field of the invention further relates to methods of treating cancer.
2. Background of the Invention
Cancer is a group of diseases characterized by uncontrolled cellular growth and, at times, spread of these “abnormal” cells from the initial site of growth to distal areas. If the spread of cancer is not controlled, death can ensue. Cancer is caused by both external factors (e.g., tobacco, infectious organisms, chemicals, and radiation) and internal factors (e.g, inherited mutations, hormones, immune conditions, and mutations that occur from metabolism). These causal factors may act together or in sequence to initiate or promote carcinogenesis. Ten or more years often pass between exposure to external factors and detectable cancer. Cancer is treated with surgery, radiation, chemotherapy, hormone therapy, biological therapy, and targeted therapy. The National Institutes of Health estimates overall costs of cancer in 2008 at $228.1 billion: $93.2 billion for direct medical costs (total of all health expenditures); $18.8 billion for indirect morbidity costs (cost of lost productivity due to illness); and $116.1 billion for indirect mortality costs (cost of lost productivity due to premature death).
There are a number of different types of cancers that affect specific organs or tissues of the body. A particularly prevalent cancer affecting the U.S. population and others worldwide is skin cancer. Malignant melanoma is a commonly diagnosed highly aggressive and drug-resistant cancer that accounts for approximately 75% of cancer skin deaths (Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun M J. Cancer statistics, 2007. CA Cancer J Clin 2007; 57: 43-66). Poor prognosis is likely related to the failure of conventional therapies to eradicate cancer cells that are responsible for resistance, invasiveness, and neoplastic progression (Schatton T, Frank M H. Cancer stem cells and human malignant melanoma. Pigment Cell Melanoma Res 2008; 21: 39-55). Oncolytic viruses are recognized as a promising novel therapy designed to reduce tumor burden by direct cell lysis resulting from virus replication and generation of infectious progeny that spreads throughout the tumor (Shen Y, Nemunaitis J. Herpes simplex virus 1 (HSV-1) for cancer treatment. Cancer Gene Ther 2006; 13: 975-992; Mathis J M, Stoff-Khalili M A, Curiel D T. Oncolytic adenoviruses—selective retargeting to tumor cells. Oncogene 2005; 24: 7775-7791). Virotherapy may also disrupt the tumor vasculature and induce anti-tumor immunity, and virotherapy also carries the promise of targeting cancer stem cells (Shen Y, Nemunaitis J. Herpes simplex virus 1 (HSV-1) for cancer treatment. Cancer Gene Ther 2006; 13: 975-992; Mathis J M, Stoff-Khalili M A, Curiel D T. Oncolytic adenoviruses—selective retargeting to tumor cells. Oncogene 2005; 24: 7775-7791; Ribacka C, Pesonen S, Hemminki A. Cancer, stem cells, and oncolytic viruses. Ann Med 2008; 40: 496-505). Originally developed to target neuronal cancers, the herpes simplex virus (HSV) oncolytic constructs were generated from HSV-1 through deletion/modification of the neurovirulence gene ICP34.5 and/or the large subunit of ribonucleotide reductase (R1). Early clinical trials have shown that oncolytic viral therapies are well tolerated, but their efficacy is modest, apparently related to poor virus replication within the tumors (Aghi M, Martuza R L. Oncolytic viral therapies—the clinical experience. Oncogene 2005; 24: 7802-7816). Accordingly, ongoing efforts have focused on improving virus replication through: (i) fusogenic alterations that increase virus uptake/spread; (ii) modulation of the tumor milieu; (iii) suppression of innate immunity or interference with virus-mediated immune evasion; (iv) expression of immunostimulatory cytokines; and (v) use of cytotoxic drugs in combinatorial therapy (Fu X, Tao L, Cai R, Prigge J, Zhang X. A mutant type 2 herpes simplex virus deleted for the protein kinase domain of the ICP10 gene is a potent oncolytic virus. Mol Ther 2006; 13: 882-890; Kurozumi K, Hardcastle J, Thakur R, Yang M, Christoforidis G, Fulci G, et al. Effect of tumor microenvironment modulation on the efficacy of oncolytic virus therapy. J Natl Cancer Inst 2007; 99: 1768-1781; Fulci G, Breymann L, Gianni D, Kurozomi K, Rhee S S, Yu J, et al. Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responses. Proc Natl Acad Sci USA 2006; 103: 12873-12878; Hu J C, Coffin R S, Davis C J, Graham N J, Groves N, Guest P J, et al. A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor. Clin Cancer Res 2006; 12: 6737-6747; Kumar S, Gao L, Yeagy B, Reid T. Virus combinations and chemotherapy for the treatment of human cancers. Curr Opin Mol Ther 2008; 10: 371-379). However, it is becoming increasingly evident that the development of oncolytic viruses with distinct molecular death functions is highly desirable.
It is apparent that there is a need in the art for an effective treatment for cancer (including, for example, melanoma due to this type of cancer's highly aggressive and drug-resistant nature, and due to the fact that there is currently no effective therapy for malignant melanoma) and for the development of efficacious oncolytic viruses.
Malignant melanoma is a highly aggressive and drug-resistant cancer. Virotherapy is a nascent therapeutic strategy based on cancer cell lysis through selective virus replication. However, its clinical efficacy is modest, apparently related to poor virus replication within the tumors. The inventors teach and disclose here for the first time that the growth compromised HSV-2 mutant delta-PK (delta-PK) has strong oncolytic activity for melanoma, which is caused in-part by a mechanism other than replication-induced cell lysis. The invention is drawn to novel methods of treating cancer using a HSV-2 virus that lacks protein kinase activity of ICP10. An oncolytic virus developed and used by the inventors is HSV-2 ICP10 PK-deleted virus (delta-PK).